| Project title |
Transcriptional Regulation of Stem Cell Differentiation |
| Summary |
A major challenge in modern biology is to understand how “cell fate decisions” are regulated in stem and progenitor cells. These decisions govern whether a particular stem or progenitor cell differentiates into one type of cell or another. This question has major implications for regenerative medicine as well as our understanding of the molecular events that lead to cancer. It is becoming increasingly clear that, in addition to genetic alterations, cancer development involves the alteration of gene expression patterns as a result of epigenetic changes (Feinberg et al., 2006). There are already several examples of epigenetic modifiers that are deregulated in cancer, e.g. MLL in leukemia (Krivtsov and Armstrong, 2007). The recent advent of “cancer epigenetic therapies”, such as those using HDAC inhibitors to treat certain types of lymphoma, have demonstrated that knowledge in this field can lead to tangible successes in cancer treatment (Yoo and Jones, 2006).
Our central hypothesis is that the deregulation of the function of a set of epigenetic modifiers, the Polycomb group proteins, during cell fate decisions is central to tumour initiation. We are currently experimentally addressing this hypothesis, as well as investigating possible interactions between Polycomb group proteins and transcription factors involved in cell fate decisions, known as cell fate transcription factors (CFTFs). The goal is that this research will lead to breakthroughs in our understanding of cell fate determination as well as cancer development. |
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Transcriptional Regulation of Cellular senescence |
| Summary |
Cellular senescence is an irreversible arrest of proliferation. It is activated when a cell encounters stress such as DNA damage, telomere shortening, or oncogene activation. Like apoptosis, it impedes tumour progression and acts as a barrier that pre-neoplastic cells must overcome during their evolution toward the full tumourigenic state. Central to cellular senescence are the p53 and pRb tumour suppressor pathways, which are activated upon cellular stress. We are studying the role of transcriptional regulators in the control of these cellular senescence pathways. Our goal is to harness this knowledge for future cancer therapies. |
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Lanigan F, Geraghty JG, Bracken AP., Transcriptional regulation of cellular senescence, Oncogene, 30, 2011, p2901–2911
Notes: [Pubmed ID: 21383691]
DOI |
Bracken AP, Helin K., Polycomb group proteins: navigators of lineage pathways led astray in cancer, Nature Reviews Cancer, 9, (11), 2009, p773 - 784
Notes: [Pubmed ID: 19851313]
DOI |
Brien GL, Bracken AP., Transcriptomics: unravelling the biology of transcription factors and chromatin remodelers during development and differentiation, Seminars in Cell and Developmental Biology, 20, (7), 2009, p835 - 841
Notes: [Pubmed ID: 19682593]
DOI |
Bracken AP, Kleine-Kohlbrecher D, Dietrich N, Pasini D, Gargiulo G, Beekman C, Theilgaard-Mönch K, Minucci S, Porse BT, Marine JC, Hansen KH and Helin K., The Polycomb Group Proteins Bind Throughout the INK4A-ARF locus and are Disassociated in Senescent Cells., Genes and Development, 21, (5), 2007, p525 - 530
Notes: [PubMed ID: 17344414
]
DOI |
Bracken AP, Dietrich N, Pasini D, Hansen KH and Helin K, Genome-wide Mapping of Polycomb Target Genes Unravels Their Roles in Cell Fate Transitions., Genes and Development, 20, (9), 2006, p1123 - 1136
Notes: [PubMed ID: 16618801]
DOI |
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Last Updated:11-FEB-2012 |